1. Field of the Invention
The present invention relates to novel compounds and anticancer drug potentiaters containing them as effective components.
2. Description of the Prior Art
Since the number of cancer patients is increasing year after year and cancer is the leading death cause today in many countries, cancer treatment is of great social interest.
Research and development regarding anticancer drugs for cancer treatment have been actively pursued and various anticancer drugs have been clinically used for therapeutic benefit. The effect of these agents steadily improves from year to year. However, in many cases, the agents do not necessarily completely control cancer growth and prolong the life of cancer patients. Furthermore, the use of multiple anticancer drugs in combination (multiple-drug treatment) have been tried in various clinical cases. However, likewise, the resulting effect is not entirely satisfactory cancer chemotherapy. Thus, development of novel therapeutic agents for the treatment of cancer from a fresh viewpoint is needed.
Development of more effective anticancer drugs or of means to deliver anticancer drugs more selectively to the target organs and tissues continues. Today, various research activities directed towards these goals are being conducted in many places throughout the world but only with increasing difficulty.
Another important aspect of cancer chemotherapy is potentiating the effects of chemotherapeutic agents. Development of potentiaters to facilitate presently available anticancer drugs, in particular for multiple drug-resistant cancers which is a serious clinical problem in cancer chemotherapy, is considered to be extremely important in cancer therapy. The background of the clinical incidence of resistance of cancer to anticancer drugs is complex. Clinically, two aspects are generally considered. The first is where the resistance is attributed to individual cancer patients. The second is where the resistance is attributed to cancer cells per se. Recently, as to the second aspect, the mechanism of tumor cell resistance has been elucidated at a molecular level and accordingly methods for therapy of this type of cancer resistance have been under investigation. Namely, a gene which is responsible for multi-drug-resistance has been recently isolated. It has been determined that this gene codes for a membrane protein, P-glycoprotein, and is expressed in multi-drug-resistant cells. It is suspected that the P-glycoprotein functions by promoting extracellular excretion of anticancer drugs and plays the central role in the mechanism of multiple-drug-resistance. Furthermore, it is suggested that the mechanism is partly common to that of the resistance to solid cancer which is by itself resistant to anticancer drugs.
Anticancer drugs primarily pass into the cell membrane to manifest their effect inside the cells; however, in drug-resistant cancer cells, anticancer drugs are discharged outside the cells due to the function of the P-glycoprotein, so that the drug concentration inside the cancer cells remains low. Consequently, the effect of the anticancer drugs is not exhibited to the fullest extent possible.
Accordingly, the present inventors consider that substances which can suppress the function of the P-glycoprotein so as to interfere with the outflow of anticancer drugs from cancer cells have ability to potentiate the effect of anticancer drugs and are particularly effective in overcoming drug resistance and thus make promising novel cancer chemotherapeutics.
In fact, Tsuruo et al. found that calcium antagonists such as verapamil prevent discharge of anticancer drugs from cancer cells and that, accordingly with the use of these calcium antagonists in combination, the effect of anticancer drugs such as adriamycin and vincristine on drug-resistant cancer cells is reinforced in vitro and in vivo. However, in the case where these calcium antagonists are used clinically for cancer patients, side effects such as hypotonia and arhythmia occur, which creates another serious problem in cancer chemotherapy. Consequently, drugs which have a stronger potentiating activity for anticancer drugs against drug-resistant cancers and manifest fewer side effects are desired.